Annals of the Rheumatic Diseases, 1978, 37, 93-97
Alclofenac and D-penicillamine Comparative trial in rheumatoid arthritis H. BERRY', L. FERNANDES', A. W. FORD-HUTCHINSON2, S. J. W. EVANS,3 AND E. B. D. HAMILTON' From the Departments of Rheumatology' and Chemical Pathology,3 King's College Hospital; and Department ofStatistics, London Hospital2 SUMMARY Forty-six patients with rheumatoid arthritis, 22 receiving D-penicillamine and 24 alclofenac, took part in a 6-month single-blind external observer trial to compare the efficacy and toxicity of these drugs in the treatment of severe rheumatoid arthritis. Both drugs were active and similar in their efficacy at 6 months as judged by clinical and laboratory measurements. Penicillamine was active therapeutically by 3 months, one month before alclofenac. 9 patients, 8 on alclofenac and one on D-penicillamine, had to stop treatment because of lack of effect or toxic effects. Skin rashes within the first week of treatment were a major problem with alclofenac and led to 6 withdrawals.
Alclofenac has been shown to have useful analgesic anti-inflammatory properties in the treatment of rheumatoid arthritis (Aylward, 1973). Further studies have suggested greater efficacy than aspirin (Aylward et al., 1974) and indomethacin (Aylward et al., 1975). It seemed appropriate to evaluate this drug in the management of severe rheumatoid arthritis. D-penicillamine, originally discovered by Abraham et al. (1942) and first used clinically by Walshe (1956) in the treatment of Wilson's disease, has been used increasingly in the treatment of severe rheumatoid arthritis. It was first validated by the multicentre study of Andrews et al. (1973). Subsequently its place has been established by the finding of comparable efficacy with gold (Huskisson et al., 1974) and azathioprine (Berry et al., 1976). In view of the now established value of penicillamine, it was used as the comparative drug in this study.
unwanted side effects described by the patients. A 'blind' observer (L.F.) assessed the severity of the disease. PATIENT SELECTION
Outpatients attending the department of rheumatology were admitted to the trial if they were over 18 years of age and had definite or classical rheumatoid arthritis, including either positive rheumatoid factor (latex titre 1/80 or more) or erosive changes on x-rays of the hands, feet or both. The disease had to be severe enough for the clinician to conventionally consider the use of gold. If the patients were receiving steroid therapy, the dosage had to have been stable for the preceding 6 months. Criteria for exclusion were (a) treatment in the preceding 6 months with gold, azathioprine, or at any time with alclofenac or D-penicillamine; (b) abnormally low white cell count or platelet count at any time; (c) evidence of renal impairment (raised blood urea or serum Methods creatinine); (d) risk of pregnancy. Informed consent was obtained from all patients at the beginning of A single-blind external observer trial was performed -the trial. at King's College Hospital. The trial supervisor (H.B.), who was aware of the treatment allocation, DRUGS was responsible for routine management, checking Alclofenac 1 g three times daily was compared with blood tests and urine analysis results, and listing penicillamine 750 mg daily reached by 250 mg increments every 4 weeks. Patients were randomly allocated to either treatment and were only stratified Accepted for publication September 10, 1977 for current corticosteroid administration. In addition Dr H. Correspondence to Berry,.Department of Rheumatology, King's College Hospital, Denmark Hill, London SE5. to the trial drugs, patients continued to receive a 93
94 Berry, Fernandes, Ford-Hutchinson, Evans, Hamilton regular dose of the anti-inflammatory/analgesic drug they had been receiving before the study; this had to have been stable for the preceding month. Only paracetamol was allowed in addition. All medication was issued through normal outpatient prescribing channels.
during the first week of the trial because of skin rash. Restarting the drug produced a skin rash again. The mean age in the penicillamine group was 56 5 years and 55 9 years in the alclofenac group and the mean duration of disease was 9 4 years and 7-7 years respectively.
ASSESSMENTS
Table 1 Patient selection
The following measurements were made at the beginning of the trial and monthly for 6 months. (a) Pain using the 20-point visual analogue scale. (b) Pain using the 4-point scale (1=nil, 2=mild, 3=moderate, 4=severe. (c) Articular index (Ritchie). (d) Grip strength (bag inflated to 30 mm repeated three times, taking the sum of the last 2 readings for each hand). (e) Ring size using the Geigy ring size measuring device. (f) Early morning stiffness measured in minutes. LABORATORY MEASUREMENTS All laboratory measurements were
made before
treatment with either penicillamine or alclofenac and at monthly intervals thereafter. The erythrocyte sedimentation rate was measured by the method of
Westergren. Total and differential white cell and platelet counts were performed by standard methods. IgM, IgG, and IgA were determined by fluoronephelometry using the Technicon AIP system, and IgE determined by radioimmunoassay (Pharmacia). Fibrinogen, ocl-acid glycoprotein, ot1-antitrypsin, x2-macroglobulin, and albumin were measured by radial immunodiffusion methods (Fahey and McKelvey, 1965) using commercial reagents (Behring diagnostic reagents, Hoechst Pharmaceuticals, Hounslow, England). Urine was tested for protein and blood on each visit. PROCEDURE Patients were assessed monthly during the study. Treatment was stopped if the white blood cell count or platelet count fell below the lower limit of normal
(white cells 4 x 109/l (4000/mm3); platelets 150 x 109/l (150 000/mm3) ). On recovery the drug was gradually reintroduced. If the problem recurred, then the patient was withdrawn from the trial, continuation of treatment representing an unreasonable risk to the patient.
Results Forty-six patients were admitted to the trial; 24 received alclofenac (18 female) and 22 penicillamine (16 female). 37 completed 26 weeks (16 on alclofenac and 21 on penicillamine: Table 1). 3 (2 on alclofenac and 1 on penicillamine) were withdrawn because of lack of effect and 6, all on alclofenac, were withdrawn
Altlofenac
Penicillamine
24 (18 females) Number of patients Mean age (years) 55 9 Mean duration of disease 7-7 (years)
22 (16 females) 56-5 94
Table 2 Clinical results (1) (mean values) Altlofenac (A)
Pain (VAS) 10-33 Initially 10-41 3m 843 4m 912 5m 6m 8-56 Pain (4 point) 2 83 Initially 2 77 3m 4m 2-56 5m 2-56 2-50 6m Articular index 19-3 Initially 19-8 3m 17-4 4m 21-0 5m 198 6m
Penici/lamine
(P)
Significance Av.P
9-38 6-81 7-29 7-47 6-95
NS
2 57 2-43 2-33 2-38 219
NS
15-5 13-3 13 3
Av. initial value
Pv. initial value
NS
Alclofenac and D-penicillamine Comparative trial in rheumatoid arthritis H. BERRY', L. FERNANDES', A. W. FORD-HUTCHINSON2, S. J. W. EVANS,3 AND E. B. D. HAMILTON' From the Departments of Rheumatology' and Chemical Pathology,3 King's College Hospital; and Department ofStatistics, London Hospital2 SUMMARY Forty-six patients with rheumatoid arthritis, 22 receiving D-penicillamine and 24 alclofenac, took part in a 6-month single-blind external observer trial to compare the efficacy and toxicity of these drugs in the treatment of severe rheumatoid arthritis. Both drugs were active and similar in their efficacy at 6 months as judged by clinical and laboratory measurements. Penicillamine was active therapeutically by 3 months, one month before alclofenac. 9 patients, 8 on alclofenac and one on D-penicillamine, had to stop treatment because of lack of effect or toxic effects. Skin rashes within the first week of treatment were a major problem with alclofenac and led to 6 withdrawals.
Alclofenac has been shown to have useful analgesic anti-inflammatory properties in the treatment of rheumatoid arthritis (Aylward, 1973). Further studies have suggested greater efficacy than aspirin (Aylward et al., 1974) and indomethacin (Aylward et al., 1975). It seemed appropriate to evaluate this drug in the management of severe rheumatoid arthritis. D-penicillamine, originally discovered by Abraham et al. (1942) and first used clinically by Walshe (1956) in the treatment of Wilson's disease, has been used increasingly in the treatment of severe rheumatoid arthritis. It was first validated by the multicentre study of Andrews et al. (1973). Subsequently its place has been established by the finding of comparable efficacy with gold (Huskisson et al., 1974) and azathioprine (Berry et al., 1976). In view of the now established value of penicillamine, it was used as the comparative drug in this study.
unwanted side effects described by the patients. A 'blind' observer (L.F.) assessed the severity of the disease. PATIENT SELECTION
Outpatients attending the department of rheumatology were admitted to the trial if they were over 18 years of age and had definite or classical rheumatoid arthritis, including either positive rheumatoid factor (latex titre 1/80 or more) or erosive changes on x-rays of the hands, feet or both. The disease had to be severe enough for the clinician to conventionally consider the use of gold. If the patients were receiving steroid therapy, the dosage had to have been stable for the preceding 6 months. Criteria for exclusion were (a) treatment in the preceding 6 months with gold, azathioprine, or at any time with alclofenac or D-penicillamine; (b) abnormally low white cell count or platelet count at any time; (c) evidence of renal impairment (raised blood urea or serum Methods creatinine); (d) risk of pregnancy. Informed consent was obtained from all patients at the beginning of A single-blind external observer trial was performed -the trial. at King's College Hospital. The trial supervisor (H.B.), who was aware of the treatment allocation, DRUGS was responsible for routine management, checking Alclofenac 1 g three times daily was compared with blood tests and urine analysis results, and listing penicillamine 750 mg daily reached by 250 mg increments every 4 weeks. Patients were randomly allocated to either treatment and were only stratified Accepted for publication September 10, 1977 for current corticosteroid administration. In addition Dr H. Correspondence to Berry,.Department of Rheumatology, King's College Hospital, Denmark Hill, London SE5. to the trial drugs, patients continued to receive a 93
94 Berry, Fernandes, Ford-Hutchinson, Evans, Hamilton regular dose of the anti-inflammatory/analgesic drug they had been receiving before the study; this had to have been stable for the preceding month. Only paracetamol was allowed in addition. All medication was issued through normal outpatient prescribing channels.
during the first week of the trial because of skin rash. Restarting the drug produced a skin rash again. The mean age in the penicillamine group was 56 5 years and 55 9 years in the alclofenac group and the mean duration of disease was 9 4 years and 7-7 years respectively.
ASSESSMENTS
Table 1 Patient selection
The following measurements were made at the beginning of the trial and monthly for 6 months. (a) Pain using the 20-point visual analogue scale. (b) Pain using the 4-point scale (1=nil, 2=mild, 3=moderate, 4=severe. (c) Articular index (Ritchie). (d) Grip strength (bag inflated to 30 mm repeated three times, taking the sum of the last 2 readings for each hand). (e) Ring size using the Geigy ring size measuring device. (f) Early morning stiffness measured in minutes. LABORATORY MEASUREMENTS All laboratory measurements were
made before
treatment with either penicillamine or alclofenac and at monthly intervals thereafter. The erythrocyte sedimentation rate was measured by the method of
Westergren. Total and differential white cell and platelet counts were performed by standard methods. IgM, IgG, and IgA were determined by fluoronephelometry using the Technicon AIP system, and IgE determined by radioimmunoassay (Pharmacia). Fibrinogen, ocl-acid glycoprotein, ot1-antitrypsin, x2-macroglobulin, and albumin were measured by radial immunodiffusion methods (Fahey and McKelvey, 1965) using commercial reagents (Behring diagnostic reagents, Hoechst Pharmaceuticals, Hounslow, England). Urine was tested for protein and blood on each visit. PROCEDURE Patients were assessed monthly during the study. Treatment was stopped if the white blood cell count or platelet count fell below the lower limit of normal
(white cells 4 x 109/l (4000/mm3); platelets 150 x 109/l (150 000/mm3) ). On recovery the drug was gradually reintroduced. If the problem recurred, then the patient was withdrawn from the trial, continuation of treatment representing an unreasonable risk to the patient.
Results Forty-six patients were admitted to the trial; 24 received alclofenac (18 female) and 22 penicillamine (16 female). 37 completed 26 weeks (16 on alclofenac and 21 on penicillamine: Table 1). 3 (2 on alclofenac and 1 on penicillamine) were withdrawn because of lack of effect and 6, all on alclofenac, were withdrawn
Altlofenac
Penicillamine
24 (18 females) Number of patients Mean age (years) 55 9 Mean duration of disease 7-7 (years)
22 (16 females) 56-5 94
Table 2 Clinical results (1) (mean values) Altlofenac (A)
Pain (VAS) 10-33 Initially 10-41 3m 843 4m 912 5m 6m 8-56 Pain (4 point) 2 83 Initially 2 77 3m 4m 2-56 5m 2-56 2-50 6m Articular index 19-3 Initially 19-8 3m 17-4 4m 21-0 5m 198 6m
Penici/lamine
(P)
Significance Av.P
9-38 6-81 7-29 7-47 6-95
NS
2 57 2-43 2-33 2-38 219
NS
15-5 13-3 13 3
Av. initial value
Pv. initial value
NS
